Cryptosporidium is a leading cause of diarrhea-associated morbidity and mortality in young children. Currently, there is no fully effective drug to treat cryptosporidiosis and a complete lack of vaccine to prevent disease. For a long time, progress in the field of Cryptosporidium research has been hindered due to unavailability of methods to propagate the parasite, lack of efficient animal infection models and most importantly, the absence of technology to genetically manipulate the parasite. The recent advent of molecular genetics has been transformative for Cryptosporidium research, and is facilitating our fundamental understanding of parasite biology, and accelerating the pace of drug discovery. This review summarizes recent advancements in genetic manipulation and its applications for studying parasite gene function, host-parasite interactions and discovery of anti-cryptosporidial drugs.